The transdermal delivery of drugs, by diffusion through the epidermis, offers improvements over more traditional delivery methods, such as subcutaneous injections and oral delivery. Transdermal drug delivery by passive diffusion avoids the hepatic first pass effect encountered with oral drug delivery. Transdermal drug delivery also eliminates patient discomfort associated with subcutaneous injections. In addition, transdermal delivery can provide more uniform concentrations of drug in the bloodstream of the patient over time due to the extended controlled delivery profiles of certain patches. The term "transdermal" delivery, broadly encompasses the delivery of an agent through a body surface, such as the skin, mucosa, or nails of an animal.
The skin functions as the primary barrier to the transdermal penetration of materials into the body and represents the body's major resistance to the transdermal delivery of therapeutic agents such as drugs. To date, efforts have been focussed on reducing the physical resistance or enhancing the permeability of the skin for the delivery of the therapeutic agent by means of passive diffusion. Various methods for increasing the rate of transdermal drug diffusion have been used. For example, drug-impermeable backing layers made of metal, plastic and other materials have been employed in skin patches in order to limit diffusion of drugs away from the skin, increase the hydration of the skin and, thereby, increase the diffusion of drugs through the skin. Increases in the rate of absorption of agents through the skin have been produced by varying the temperature and the relative humidity of the atmosphere adjacent to the skin. Other efforts have been directed at abrading or piercing the skin by mechanically disrupting its outermost stratum corneum layer. Chemical absorption promoters (also referred to as flux enhancers or permeation enhancers) have also been utilized, both as integral components of transdermal therapeutic drug delivery devices compositions or applied to the skin as a pretreatment step before applying the transdermal patch.
The utility of fatty acid permeation enhancers in passive transdermal drug delivery has been previously recognized. (see, for example, U.S. Pat. Nos. 5,045,553 and 5,023,085 (fatty acid with additional cycloketone). Similarly, U.S. Pat. Nos. 5,069,909 (for buprenorphine), 5,001,139 and 4,892,737 disclose the use of fatty acid esters in mixtures with other enhancers for passive transdermal delivery. More generally, C.sub.5 -C.sub.30 aliphatic monocarboxylic acids are disclosed as transdermal drug permeation enhancers in U.S. Pat. No. 4,731,241 for the passive delivery of Nethoxycarbonyl-3-morpholino sydnonimine. U.S. Pat. No. 4,892,737 utilizes a mixture of quaternary ammonium salts with saturated and unsaturated aliphatic carboxylic acids for the passive transdermal electrotransport of agents. U.S. Pat. No. 4,882,163 passively delivers monoxidine with the aid of an alkyl aliphatic acid of at least 12 C-atoms. In U.S. Pat. No. 4,637,930, C.sub.6 -C.sub.12 fatty acid esters are used for the delivery of nicardipine hydrochloride.
A composition for the passive delivery of salicylic acid, which comprises aliphatic diols, an ester of a mono- or polyhydric alcohol and a saturated fatty acid is disclosed in published PCT patent application WO 90/08507. A composition containing salicylic acid, an aliphatic 1,2-diol such as propane- or butane-diol, and a fatty oil, such as triglycerides and their fatty acid derivatives, is disclosed in published PCT patent application WO 89/00853. U.S. Pat. Nos. 4,605,670 and 5,128,376, in addition, disclose the passive percutaneous administration of an active agent in a composition containing a mixture of (1) an ester of a C.sub.7 -C.sub.18 aliphatic acid and an alcohol, a C.sub.8 -C.sub.26 aliphatic monoalcohol, or mixtures thereof, and (2) C.sub.4 -C.sub.6 cyclic amides such as pyrrolidones, and diols, triols, or mixtures thereof.
These passive methods have generally had only limited success in significantly increasing the transdermal flux of drug.
Transdermal drug permeation rates (fluxes) can also be increased over that obtained with passive diffusion by employing electrically assisted, ie, electrotransport delivery. The term "electrotransport" as used herein refers to delivery of an agent through a body surface with the assistance of an electrical field. Electrotransport, thus, refers generally to the passage of an agent through a body surface, such as the skin, mucous membranes, or nails, which is at least partially induced by applying an electrical current through the surface. Many therapeutic agents, including drugs, may be introduced into the human body by electrotransport. The electrotransport of an agent through a body surface may be attained by one or more of several known phenomena. One widely used electrotransport phenomenon is iontophoresis, which involves the electrically induced transport of charged ions. Electroosmosis, another type of electrotransport, involves the movement of a liquid, which liquid contains one or more therapeutic agent(s) dissolved therein, through a biological membrane under the influence of an electrical field. Electroporation, still another type of electrotransport, involves the movement of an agent through transiently-created pores formed in a biological membrane under the influence of an electric field. When any given agent is electrotransported, more than one of these phenomena, including the phenomenon of passive diffusion, may occur simultaneously to some extent. The term electrotransport, as used herein, is given its broadest possible interpretation to include the electrically induced or enhanced transport of charged species, uncharged species, or mixtures thereof, regardless of the specific mechanism(s) by which the agent(s) is(are) actually transported.
Electrotransport devices require at least two electrodes, both being in electrical contact with some portion of the skin, nails, mucous membrane, or other membrane surfaces of the body. One electrode, commonly referred to as the "donor" or "active" electrode, is the electrode from which the therapeutic agent, such as a drug or prodrug, is delivered into the body. The other electrode, typically termed the "counter" or "return" electrode, serves to close the electrical circuit through the body. For example, if a cationic (ie, a positively charged) agent is to be delivered, the anode will be the active or donor electrode while the cathode is the counter electrode. Alternatively, if the agent to be delivered is an anion, i.e. a negatively charged ion, the cathode will be the donor electrode while the anode is the counter electrode. When anionic and cationic drugs need to be delivered at the same time, both the anode and cathode may be used for this purpose and the anionic drug placed in the cathode while the cationic drug is placed in the anode. In addition, electrotransport delivery devices include an electrical power source, typically in the form of one or more batteries, and optionally electrical control circuitry which regulates the flow of electric current through the electrodes and thereby the rate of drug delivery. Alternatively, the power may be supplied, at least in part, by a galvanic couple formed by contacting two electrodes made of dissimilar materials. A complete electrical circuit is formed by electrically contacting one pole of the power source to the donor electrode, the donor electrode to the body, the body to the counter electrode, and the counter electrode to the opposite pole of the power source.
The donor electrode typically includes a reservoir containing a solution of the agent or drug to be delivered. The donor reservoir may take the form of a pouch, a cavity, a porous sponge, a pad, and a pre-formed gel body, among others. The counter electrode likewise typically includes a reservoir containing a biocompatible electrolyte salt solution. Such reservoirs are electrically connected to the anode or cathode of the electrotransport device to provide either a fixed or a renewable source of one or more therapeutic agents or drugs.
It is known that electrotransport drug flux is roughly proportional to the level of electric current applied by the device. However, there is a limit to the current density (current density is the level of electric current (mA) applied by the device divided by the skin contact area (cm.sup.2) of the electrodes) which may be comfortably tolerated by a patient. This limit on the level of current density which may be comfortably tolerated by a patient becomes more problematic as the size of the electrotransport system and, therefore, the skin contact areas of the electrodes, is reduced, ie, for electrotransport systems which are designed to be wearable. Thus, there is a limit to the level of electric current which may be applied by any electrotransport device of a given size and this current limit becomes lower as the size or the skin contact area of the device is reduced. In certain instances, electrotransport devices operating at these current limits have been unable to deliver therapeutically effective amounts of drug. In those cases, the incorporation of a permeation enhancer into the electrotransport device may increase the amount of the agent delivered to adequate levels.
In the context of this application, the term "permeation enhancer" includes absorption promoters and surfactants and broadly describes a chemical species which either reduces the physical resistance of a body surface to the passage of an agent therethrough, alters the ionic selectivity of the body surface, increases the electrical conductivity or the permeability of the body surface, and/or increases the number of pathways therethrough. The use of electrotransport enhancers may help reduce the size of the electrotransport device by requiring a reduced electrical potential (ie, voltage) to generate a particular level of electric current (ie, mA) through the skin and thereby reduce the size and/or number of batteries needed to power the device. A reduction in the size of the device also improves patient comfort, and a reduction in the number of batteries reduces the cost of the device.
A limited number of permeation enhancers for the electrotransport delivery of therapeutic agents have been disclosed in the literature. Ethanol has been utilized as an electrotransport enhancer for polypeptides. See Srinivasan et al, J. Pharm. Sci. 79(7):588-91 (1990). In U.S. Pat. No. 4,722,726 to Sanderson et al., the skin surface is treated with an ionic surfactant (eg, sodium lauryl sulfate) to reduce competition with tissue ions migrating outwardly through the skin. U.S. Pat. No. 5,023,085 to Francoeur et al. discloses the use of unsaturated C.sub.14 -C.sub.20 acids, alcohols, amines, and esters, along with ketones for the iontophoretic delivery of certain drugs. Published PCT Patent Application WO91/16077 discloses the use of fatty acids, such as oleic acid, lauric acid, capric acid, and caprylic acid, as penetration enhancers for the iontophoretic delivery of drugs. European Patent Application 93/300198.4 discloses delivering therapeutic agents transdermally by iontophoresis with the aid of a broadly described group of "lipid modifiers". The modifiers are generally described as having a C.sub.5 -C.sub.28 aliphatic chain and moieties such as hemiacetals amids, acetals, alcohols, carboxylic acids, esters, and others, but containing no more than 50 to 60 carbon atoms. Only a few dioxolanes, an aliphatic carbonate, and a pyrrolidone are exemplified.
Many drugs exist in both free acid/base form and a salt form. For example, a base drug may exist in either free base form or in salt form, eg, an acid addition salt. One example of a base drug is lidocaine. In free base form, lidocaine is an amine. Lidocaine is also available as a hydrochloride acid addition salt. Conversely, an acid drug may exist in either free acid form or in the form of a salt, eg, a base addition salt. One example of an acid drug is salicylic acid. This drug also exists as a salt, ie, sodium salicylate. In general, the salt form of a drug is preferred over the free acid or free base form for electrotransport delivery since the salt form generally has much better water solubility and water is the preferred liquid solvent for electrotransport delivery due to its excellent biocompatability. An "acid form" of a drug or other therapeutic agent, as used herein, refers to a form of the agent which is a Lewis acid, i.e. any form of the agent which can attach itself to a molecule with an unshared pair of electrons. Similarly, a "base form" of a drug or other therapeutic agent, as used herein, refers to a form of the agent which possesses an unshared pair of electrons.
In general, many drugs exist in both (1) a salt form, and (2) either a free base or acid form. For example, a drug having an amino group may have an R.sub.3 N base form, e.g. lidocaine, or a R.sub.3 N.HCl acid addition salt form, e.g. lidocaine hydrochloride, in which a hydrogen atom is associated with, or weakly bonded to, the nitrogen atom of the amino moiety. The base form generally has poor water solubility. This is undesirable in electrotransport systems since water is the preferred liquid solvent for forming a solution of the drug to be delivered by electrotransport. Although the salt forms of drugs are likely to have higher water solubility, the pH produced by the salt form of the drug may not be optimal from the strandpoint of transdermal drug flux. For example, human skin exhibits a degree of permselectivity to charged ions which is dependant upon the pH of the donor solution of an electrotransport device. For anodic donor reservoir solutions, transdermal electrotransport flux of a cationic species (ie, a cationic drug) is optimized when the pH of the donor solution is about 6 to 9, and more preferably about 7.5 to 8. For cathodic donor reservoir solutions, transdermal electrotransport flux of an anionic species (ie, an aninoic drug) is optimized when the pH of the donor solution is about 3 to 6, and more preferably about 3.5 to 5.
A problem which arises with the addition of pH-altering species (eg, an acid or a base) to the drug solution in an electrotransport device is that extraneous ions having the same charge (ie, same sign charge) as the drug are introduced into the solution. These ions generally compete with the therapeutic agent ions for electrotransport through the body surface. For example, the addition of sodium hydroxide to lower the pH of a cationic drug-containing solution will introduce sodium ions into the solution which will compete with the cationic drug for delivery by electrotransport into the patient, and thereby makes the electrotransport delivery less efficient since it takes more electric current to delivery a set amount of drug. A similar competing ion effect can be seen with the addition of permeation enhancers in the form of salts. For example, the addition of sodium laurate as a permeation enhancer to a cationic drug-containing reservoir composition will have two opposing effects. The laurate groups will increase skin permeability, and hence increase the drug delivery rate. On the other hand, the sodium ions will compete with the cationic drug for electrotransport through the body surface and, thus, reduce the efficiency of drug delivery. The sodium ions, in this context, are termed "competing ions". As used herein, the term "competing ions" refers to ionic species having the same charge as the agent to be delivered by electrotransport, and which may take the place of the agent and be delivered through the body surface in its place. Similarly, agents which are used to buffer the pH of a donor reservoir solution can likewise result in the addition of competing ions into the donor reservoir which results in lower efficiency electrotransport drug delivery, ie, less drug is delivered per unit of electrical current applied by the device due to competing ions carrying the current as opposed to the drug ions.